Novel separation agent for separating optical isomer and method for preparation thereof

ABSTRACT

A method of producing a novel separating agent for separating enantiomeric isomers, characterized by including: a step of supporting an optically active polymer compound and a compound having an asymmetric structure of a molecular weight of 1,000 or less on a carrier using a solvent; a step of removing the solvent; and a step of removing the compound having the asymmetric structure of the molecular weight of 1,000 or less by washing.

TECHNICAL FIELD

[0001] The present invention relates to a novel separating agent forseparating enantiomeric isomers, a method of producing the same, and aseparation method for enantiometric isomers using the same, inparticular, a separation method for enantiomeric isomers withchromatography. The present invention provides a separation technique ofthe enantiomeric isomers, which enable optical resolution of chiralcompounds with high separation coefficient in analyses of medicines,foods, agricultural chemicals, fragrant materials, and the like.

BACKGROUND ART

[0002] Many organic compounds have enantiomeric isomers havingcompletely the same physical and chemical properties, but differing in aphysiological activity. This is attributable to the following. In mostcases, proteins or glucides per se constituting a living being arecomposed of only one of the enantiomeric isomers, and for this reason,any difference arises in the manner of acting on the other enantiomericisomer, resulting in a difference in the physiological activity. Inparticular, in many cases, there are significant differences in medicalproperty and toxicity between the enantiomeric isomers of thepharmaceuticals, and this problem is recognized as a significant problemin the field of pharmaceuticals. The Ministry of Health, Labour andWelfare of Japan prescribes in the Guideline for the Production ofMedicines that “in the case where the drug is a racemi form, it isdesirable that studies on the dynamic behaviors of absorption,distribution, metabolism and excretion be made on each enantiomericisomer”.

[0003] Since the enantiomeric isomers have completely the same physicaland chemical properties, for example, the physical properties such as aboiling point, a melting point or a solubility, as described above, theycannot be analyzed by ordinary separation means. For this reason,extensive investigations have been made on techniques for analyzing awide variety of enantiomeric isomers in a simple manner and with highprecision. As a result, an optical resolution method by high performanceliquid chromatography (HPLC), in particular, an optical resolutionmethod using an enantiomeric isomer separation column for HPLC has beendeveloped as an analyzing method that meets those requirements. Theenantiomeric isomer separation column defined herein uses an asymmetryidentifying agent itself or a chiral immobilizing phase having theasymmetry identifying agent supported on a suitable carrier.

[0004] As examples of the chiral immobilizing phase, optically activepoly(triphenylmethyl methacrylate) (cf., JP-A 57-150432), cellulose andamylose derivatives (cf., JP-A 60-40952, JP-A 60-108751, JP-A 60-142930and JP-A 63-178101), ovomucoid which is a protein (JP-A 63-307829), andthe like have been developed. It is known that, of those many chiralimmobilizing phases for HPLC, a column for enantiomeric isomerseparation having the cellulose or amylose derivatives supported onsilica gel has a high asymmetry identification ability to a very widevariety of compounds (for example, Okamoto et al., Angew. Chem. Int.Ed., 1998, 37, 1020).

[0005] In the case of aiming at analyses such as an optical puritymeasurement, it has been desired that as many unidentified enantiomericisomer compounds as possible can be separated by as few kinds aspossible of enantiomeric isomer separation columns. As a result, theabove-mentioned column for enantiomeric isomer separation having thecellulose or amylose derivatives supported on the silica gel has beenaccepted as practical separation media.

[0006] In recent years, studies on a liquid preparative chromatographyfor optically active substances on an industrial scale in a combinationof a chiral immobilizing phase for HPLC and a simulated moving bedmethod have been developed (Phrarm. Tech. Japan, 12, 43 (1996). In suchstudies, not only analysis, but also preparative separation, namely,chromatographic separation as production means, are noted.

[0007] For that purpose, in order to not only merely perform base lineseparation, but improve a productivity of the preparative chromatographyand decrease a production cost, it is demanded to develop a chiralimmobilizing phase that enables the further separation of a targetcompound for the limited, specified preparative separation, that is, hasa value of separation coefficient a as high as possible.

[0008] On the other hand, a molecular imprinting method is known as amethod of specifically identifying the specific target compound. Themost popular method in general production methods for a moleculartemplate is that the target compound (guest) and a monomer forperforming non-conjugated-bond-type interaction therewith are reacted ina test tube using a crosslinking agent or the like for polymerization,thereby obtaining a polymer compound (host). Further, a method ofobtaining a host by mixing the guest and a polymer and subjecting thepolymer to a crosslinking reaction in an interaction state is known (forexample, G. Wulff et al., Angew. Chem., 1972, 84, 364).

[0009] A filler for chromatography obtained by such molecular imprintinghas a high identification ability to a guest. However, it is known thatsuch a filler is extremely high in degree of adsorption to a guest, andas a result, the corresponding elution peak shows a widely extendedform. This is not satisfactory in terms of chromatography efficiency.Further, the polymer compound obtained by the molecular imprintingmethod cannot include a dissolution operation that may decompose aprepared template. For this reason, the polymer compound is preparedinto the filler for chromatography by pulverization processing or thelike. However, an operation such as classification is complicated, and aparticle size is not uniform, resulting in decrease in chromatographyefficiency. For the above reason, the filler for chromatography obtainedby the technique using the molecular imprinting method has not been yetput into practical use.

[0010] A purpose of the present invention is to a process for producinga novel separating agent for separating enantiomeric isomers to obtain aseparating agent for separating enantiomeric isomers, which is greatlyimproved in separation efficiency to an objective compounds forseparation.

[0011] Another purpose of the present invention is to provide aseparating agent for separating enantiomeric isomers, which has agreatly improved separation performance to a compound to be separatedand can separate compounds that could not conventionally be separated.

[0012] Still another purpose of the present invention is to provide animmobilizing phase for chromatography or an immobilizing phase forcontinuous liquid preparative chromatography, using the separating agentfor separating enantiomeric isomers, and a separation method forenantiomeric isomers using the separating agent for separatingenantiomeric isomers.

DISCLOSURE OF THE INVENTION

[0013] The present inventors have found that a separation ability isgreatly improved by improving a separating agent for separatingenantiomeric isomers in place of selective use of a general-purposedeveloping solvent conventionally used, specifically improving theseparating agent for separating enantiomeric isomers using a compoundhaving an asymmetric structure of a molecular weight of 1,000 or less,as a method of increasing the separation ability of the separating agentfor separating enantiomeric isomers.

[0014] More specifically, according to the present invention, there isprovided a method of producing a novel separating agent for separatingenantiomeric isomers, characterized by including adding a compoundhaving an asymmetric structure of a molecular weight of 1,000 or less insupporting an optically active polymer compound on a carrier.

[0015] Further, according to the present invention, there is provided amethod of producing a novel separating agent for separating enantiomericisomers, characterized by including: a step of supporting an opticallyactive polymer compound and a compound having an asymmetric structure ofa molecular weight of 1,000 or less on a carrier using a solvent; and astep of removing the solvent.

[0016] Further, according to the present invention, there is provided amethod of producing a novel separating agent for separating enantiomericisomers, characterized by including: a step of supporting an opticallyactive polymer compound and a compound having an asymmetric structure ofa molecular weight of 1,000 or less on a carrier using a solvent; a stepof removing the solvent; and a step of removing the compound having theasymmetric structure of the molecular weight of 1,000 or less bywashing.

[0017] Further, according to the present invention, there is provided amethod of producing a novel separating agent for separating enantiomericisomers, characterized by including: a step of supporting an opticallyactive polymer compound on a carrier using a solvent; a step ofadditionally supporting a compound having an asymmetric structure of amolecular weight of 1,000 or less on the carrier; and a step of removingthe solvent.

[0018] Further, according to the present invention, there is provided amethod of producing a novel separating agent for separating enantiomericisomers, characterized by including: a step of supporting an opticallyactive polymer compound on a carrier using a solvent; a step ofadditionally supporting a compound having an asymmetric structure of amolecular weight of 1,000 or less on the carrier; a step of removing thesolvent; and a step of removing the compound having the asymmetricstructure of the molecular weight of 1,000 or less by washing.

[0019] Further, according to the present invention, there is provided aseparating agent for separating enantiomeric isomers, including anoptically active polymer compound supported on a carrier, from which acompound having an asymmetric structure of a molecular weight of 1,000or less added as a production raw material and supported is removed.

[0020] Further, according to the present invention, there is provided animmobilizing phase for a chromatography using the separating agent forseparating enantiomeric isomers or an immobilizing phase for acontinuous liquid preparative chromatography using the separating agentfor separating enantiomeric isomers or a separation method forenantiomeric isomers using the separating agent for separatingenantiomeric isomers.

BEST MODE FOR CARRYING OUT THE INVENTION

[0021] A method of producing a novel separating agent for separatingenantiomeric isomers of the present invention is described.

[0022] The production method of the present invention includes a step ofadding a compound having an asymmetric structure of a molecular weightof 1,000 or less in supporting an optically active polymer compound on acarrier, and a production method including the following steps can beexemplified as the production method including the above step.

[0023] Firstly, in a first step, an optically active polymer compoundand a compound having an asymmetric structure of a molecular weight of1,000 or less are supported on a carrier using a solvent. Here, in thepresent invention, the optically active polymer compound is directlysupported on the carrier. However, the compound having the asymmetricstructure of the molecular weight of 1,000 or less is not directlysupported on the carrier, but is indirectly supported on the carrier byphysically or chemically bonding it to the optically active polymercompound.

[0024] In this step, the following methods can be applied:

[0025] (1) a method of preparing a solvent solution of an opticallyactive polymer compound and the compound having the asymmetric structureof the molecular weight of 1,000 or less, and bringing the solution andthe carrier in contact with each other by a method of immersing thecarrier in the solution, a method of applying the solution to thecarrier, or the like, thereby supporting it on the carrier; and

[0026] (2) a method of preparing the solvent solution of the opticallyactive polymer compound, contact-supporting the solution on the carrierby a method of immersing the carrier in the solution, and dissolving thecompound having the asymmetric structure of the molecular weight of1,000 or less in the solution, or after preparation of the solventsolution, adding the solvent solution of the compound having theasymmetric structure of the molecular weight of 1,000 or less to thesolution, thereby supporting it on the carrier.

[0027] The term “supporting” used herein means that an optically activepolymer compound and a compound having an asymmetric structure of amolecular weight of 1,000 or less are fixed to the carrier. Thisfixation is performed by physical adsorption and/or chemical bondingbetween the optically active polymer compound and a compound having anasymmetric structure of a molecular weight of 1,000 or less, and acarrier.

[0028] The physical adsorption means that the compound is adsorbed on asurface of the carrier and/or inside fine pores of the carrier.

[0029] The chemical bonding includes bonding between a carrier and anoptically active polymer compound, bonding between a part of theoptically active polymer compound physically adsorbed on the carrier,bonding between remaining optically active polymer compound and thecompound having the asymmetric structure of the molecular weight of1,000 or less, and chemical bonding between the carrier and theoptically active polymer compound by reaction with a crosslinking agent,reaction with a radical generator or light irradiation (irradiation withradiation such as γ-rays, or irradiation with electromagnetic waves suchas microwave).

[0030] When chemically bonding the carrier and the optically activepolymer compound, it is desirable to perform chemical bonding before orafter a step of removing the compound having the asymmetric structure ofthe molecular weight of 1,000 or less as a post-step.

[0031] Examples of the optically active polymer compound used in thepresent invention include polymers or copolymers of (meth)acrylates or(meth)acrylamides that do not have optically active substituents,(meth)acrylates or (meth)acrylamides having the optically activesubstituents, styrene, acetylene or the like, polysaccharides or theirderivatives, peptides, and proteins.

[0032] Of those, the polymer compounds having the asymmetryidentification ability to a compound to be separated are preferable. Inparticular, the polymers or copolymers of (meth)acrylates or(meth)acrylamides, polysaccharides and their derivatives, and proteinsthat are known to have the asymmetry identification ability arepreferable, polymers or copolymers of (meth)acrylamides or(meth)acrylates, polysaccharides and their derivatives having opticallyactive substituents at side chains are more preferable, andpolysaccharide derivatives are most preferable.

[0033] Note that, the (meth)acrylates used in this specification meanacrylates and methacrylates, and the (meth)acrylamides used in thisspecification mean acrylamides and methacrylamides.

[0034] As a polysaccharide, any synthetic polysaccharide, any naturalpolysaccharide, and any modified natural polysaccharide maybe used solong as they have an optical activity. Those which have a highregularity in the binding form are more desired.

[0035] There are exemplified β-1,4-glucan (cellulose), α-1,4-glucan(amylose, amylopectin), α-1,6-glucan (dextran), β-1,6-glucan (busturan),β-1,3-glucan (for example, cardran, schizophyllan, etc.), α-1,3-glucan,β-1,2-glucan (Crown Gall polysaccharide), β-1,4-galactan, β-1,4-mannan,α-1,6-mannan, β-1,2-fructan (inulin), β-2,6-fructan (levan),β-1,4-xylan, β-1,3-xylan, β-1,4-chitosan, α-1,4-N-acetylchitosan(chitin), pullulan, agarose, alginic acid, and the like. Also, thepolysaccharide includes starch containing amylose.

[0036] Among those, cellulose, amylose, β-1,4-xylan, β-1,4-chitosan,chitin, β-1,4-mannan, inulin, and cardran, which are readily availableas the polysaccharide having high purity, are preferred. Cellulose andamylose are particularly preferred.

[0037] These polysaccharides have a number-average degree ofpolymerization (an average number of pyranose rings or furanose ringscontained in one molecule) of at least 5, preferably at least 10, orpreferably 1,000 or less in view of ease of handling, though there is noparticular limitation in the upper limit thereof.

[0038] The polysaccharide derivative is a compound being combined with acompound having a functional group being reactive with part or all ofthe hydroxyl groups of the polysaccharide through an ester bond, anurethane bond or an ether bond.

[0039] The compound having a functional group capable of reacting withhydroxyl group can be any compound so long as it is a compound havingleaving groups such as substituted or unsubstituted aromatic, aliphaticor alicyclic carboxylic acids, acid halides, acid anhydrides, carboxylicacid derivatives such as acid ester, substituted or unsubstitutedaromatic, aliphatic or alicyclic isocyanic acid derivatives, alcohols,and other compounds. The compound may have or may not have opticallyactive groups.

[0040] Preferable polysaccharide derivatives are polysaccharide esterderivatives and carbamate derivatives, and polysaccharide esterderivatives and carbamate derivatives having 0.1 or more, per glucoseunit, of ester bond or urethane bond are particularly preferable.

[0041] The amount of the optically active polymer compound used is suchan amount that the amount of the compound supported on a carrier withrespect to a carrier mass preferably corresponds to 1 to 100 mass %,more preferably 5 to 60 mass %, and most preferably 10 to 40 mass %.

[0042] The compound having the asymmetric structure of the molecularweight of 1,000 or less used in the present invention includes thefollowing (I) and (II).

[0043] (I) A compound to be separated in the case of being used as aseparating agent for separating enantiomeric isomers, or its similarlystructured compound. The “similarly structured compound” used herein isa compound in which a functional group is similar to that of thecompound to be separated, the number of methylene chains increases ordecreases, the number of substituents increases or decreases, a positionof the functional group differs, and a kind of functional group differsfrom the compound to be separated and which accordingly has such astructure that a molecular size is, for example, larger by about 1 to 5carbon atoms or smaller by about 1 to 5 carbon atoms. Examples of thesimilarly structured compound, with respect to 1-phenyl-2-propanol,include 1-phenylethanol, 2-phenyl-2-propanol, 1-phenyl-2-butanol,2-phenyl-2-butanol, 3-phenyl-2-butanol, 1-substituted phenyl-2-propanol,1-(1-naphthyl)-2-propanol, 1-(2-pyridyl)-2-propanol, and1-cyclohexyl-2-propanol. Example of the similarly structured compound,with respect to 1-(1-naphthyl) -ethanol, include 1- (9-anthryl)-ethanol.

[0044] Besides, the “similarly structured compound” includes compoundsin which environmental conditions around the asymmetric carbon aresimilar.

[0045] (II) A compound to be separated in the case of being used as aseparating agent for separating enantiomeric isomers, or a compoundother than a similarly structured compound thereof, preferably acompound having a cyclic structure of a molecular weight of 40 to 1,000,preferably 60 to 600.

[0046] Preferable compounds (I) and (II) are compounds having polarfunctional group such as a heteroatomic group, e.g., a hydroxyl group, acarbonyl group, an amino group or a carboxyl group, compounds having afunctional group related to π-electron interaction, such as benzenering, racemi form (±), and optically active substance (+) or (−) arepreferable.

[0047] The compound (I) has a molecular weight of 40or more, preferably60 to 1,000, and more preferably 100 to 500.

[0048] The compound having the asymmetric structure of the molecularweight of 1,000 or less is used in an amount of preferably 0.01 to1,000mass %, more preferably 0.01 to 200 mass %, and most preferably 0.1to 30 mass %, based on the mass of the optically active polymer compoundsupported on a carrier.

[0049] The carrier used in the present invention includes organic porouscarriers and inorganic porous carriers. The inorganic porous carriersare preferable. Suitable examples of the organic porous carrier includepolymer substances including polystyrenes, polyacrylamides,polyacrylates, or the like. Suitable examples of the inorganic porouscarrier include silica, alumina, magnesia, glass, kaolin, titaniumoxide, silicates and hydroxyapatites.

[0050] Silica gel is a particularly preferable carrier. The silica gelhas a particle diameter of 0.1 μm to 10 mm, preferably 1 μm to 300 μm,and most preferably 1 to 100 μm, and an average pore diameter of 10 Å to100 μm, and preferably 50 to 50,000 Å. Surface treatment may be appliedto the surface of silica gel in order to eliminate effects of residualsilanol, but there is no problem even though the surface treatment isnot applied to the surface.

[0051] The solvent used in the present invention may be anygenerally-used organic solvent so long as it can dissolve the opticallyactive polymer compound and the compound having the asymmetric structureof the molecular weight of 1,000 or less.

[0052] Examples of the solvent include ketone solvents such as acetone,ethyl methyl ketone or acetophenone; ester solvents such as ethylacetate, methyl acetate, propyl acetate, methyl propionate or phenylacetate; ether solvents such as tetrahydrofuran, 1,4-dioxane, diethylether, tert-butyl methyl ether or anisole; amide solvents such asN,N-dimethylformamide; imide solvents such asN,N-dimethylimidazolidinone; halogen solvents such as chloroform,methylene chloride, carbon tetrachloride, 1,2-dichloroethane orpentafluoroethanol; hydrocarbon solvents such as pentane, petroleumether, hexane, heptane, octane, benzene, toluene, xylene or mesitylene;alcohol solvents such as methanol, ethanol, propanol or butanol; acidsolvents such as acetic acid, trifluoroacetic acid or formic acid;phenol solvent such as phenol or catechol; and amine solvents such asdiethylamine, triethylamine, pyridine or aniline.

[0053] In preparing the optically active polymer compound and thecompound having the asymmetric structure of the molecular weight of1,000 or less using such a solvent, a solution concentration is notparticularly limited, and is determined considering ease ofcontact-supporting treatment with the carrier, and removal treatment ofa solvent in a post-step.

[0054] A solvent used to support the optically active polymer compoundand the compound having the asymmetric structure of the molecular weightof 1,000 or less on the carrier is removed in the next step.

[0055] In the solvent removal treatment in this step, the opticallyactive polymer compound is still directly supported on the carrier, andthe compound having the asymmetric structure of the molecular weight of1,000 or less maintains the state of being indirectly supported on thecarrier.

[0056] In the next step, the optically active polymer compound and thecompound having the asymmetric structure of the molecular weight of1,000 or less are washed in the state where they are supported on thecarrier, thereby removing the compound having the asymmetric structureof the molecular weight of 1,000 or less.

[0057] The washing step can adopt, for example, a method of refluxingunder any temperature of 0° C. to a reflux temperature usingacetonitrile, alcohol, hexane, a mixed solvent of hexane and alcohol, orthe like.

[0058] The amount of solvent used in the case of adopting the refluxmethod is about 3 to 50 times the mass of the carrier having supportedthereon the optically active polymer compound and the compound havingthe asymmetric structure of the molecular weight of 1,000 or less.

[0059] A residual amount of the compound having the asymmetric structureof the molecular weight of 1,000 or less after the washing treatment ofthis step is, when finally formed into a separating agent for separatingenantiomeric isomers, preferably 10 mass % or less, more preferably 2mass % or less, and most preferably 0.5 mass % or less, in theseparating agent. The compound having the asymmetric structure of themolecular weight of 1,000 or less may be contained as an impurity if thecontent is less than the above value.

[0060] Further, the compound having the asymmetric structure of themolecular weight of 1,000 or less after the washing treatment of thisstep can be substantially removed as well.

[0061] A separating agent for separating enantiomeric isomers obtainedaccording to the producing method of the present invention includes anoptically active polymer compound supported on a carrier, further, fromwhich a compound having an asymmetric structure of a molecular weight of1,000 or less added as a production raw material and supported isremoved.

[0062] In the separating agent for separating enantiomeric isomersobtained according to the producing method of the present invention, thecompound having the asymmetric structure of the molecular weight of1,000 or less is the compound of the item (I) or (II), and when theenantiomeric isomers are separated using the separating agent forseparating the enantiomeric isomers, a separation performance based on aseparation coefficient (α) obtained by the following equation:

separation coefficient (α)=(holding coefficient of enantiomer heldrelatively strongly)/(holding coefficient of enantiomer held relativelyweakly)

holding coefficient (k′)=[(holding time of the enantiomer)−(deadtime)]/(dead time)

[0063] [where, the dead time is set as elution time oftri-tert-butylbenzene] is desirably shown by the following equation (A)or equation (B):

(A)α₁/α₂≧1.05(provided α₂=1.00)

(B) α₁/α₂≧1.05(provided α₂>1.00)

[0064] where α₁: a separation coefficient of the separating agent forseparating the enantiomeric isomers obtained by adding the compoundhaving the asymmetric structure of the molecular weight of 1,000 or lessin a production step, and

[0065] α₂: a separation coefficient of the separating agent forseparating the enantiomeric isomers obtained without adding the compoundhaving the asymmetric structure of the molecular weight of 1,000 or lessin the production step, in which α₂=1.00 means that the enantiomericisomers are not separated al all, and α₂>1.00 means that theenantiomeric isomers are separated.

[0066] The equation (A) shows α₂=1.00, that is, the fact that separationperformance of a compound that involves absolutely no separation in thecase of using a separating agent for separating enantiomeric isomersobtained without adding a compound having an asymmetric structure of amolecular weight of 1,000 or less in the production step is improved by5% or more in the case of using the separating agent for separatingenantiomeric isomers of the present invention.

[0067] The equation (B) shows α₂>1.00, that is, the fact that separationperformance in the case of using a separating agent for separatingenantiomeric isomers obtained without adding a compound having anasymmetric structure of a molecular weight of 1,000 or less in theproduction step is improved by 5% or more in the case of using theseparating agent for separating enantiomeric isomers of the presentinvention. In the present invention, the separation performance definedby the equation (B) is improved by preferably 10% or more, morepreferably 15% or more, and most preferably 20% or more.

[0068] The separating agent for separating enantiomeric isomers of thepresent invention can be used as an immobilizing phase forchromatography such as gas chromatography, liquid chromatography, thinlayer chromatography, supercritical chromatography or capillaryelectrophoresis. In particular, it is preferably used as the chiralimmobilizing phase for liquid chromatography. It can also be suitablyused as an immobilizing phase for continuous liquid preparativechromatography represented by a simulated moving bed chromatography. Theenantiomeric isomers can be separated with good efficiency using such aseparating agent of the present invention. Industrial Applicability

[0069] The present invention can greatly improve the separationperformance of a separating agent for separating enantiomeric isomers,and particularly, such a separating agent is suitable as an immobilizingphase for chromatography and an immobilizing phase for continuous liquidpreparative chromatography.

EXAMPLES

[0070] The present invention is described in detail based on examples,but the present invention is not limited to those examples.

[0071] A representation of the compounds described hereinafter is basedon any compound selected from the following compounds 1 to 16. Withrespect to a compound having an asymmetric structure of a molecularweight of 1,000 or less and a compound to be separated, representationof steric configuration (S,R), optical activity (D,L) and racemi form iscombined with each compound number. For example, when the compound 1 hasan S configuration, it is expressed as S-1, and when the compound 1 is aracemi form, it is expressed as racemi form-1.

Example 1

[0072] (1) Surface Treatment of Carrier (Silica Gel)

[0073] Porous silica gel (particle diameter: 7 μm, micropore: 1,000 Å)was reacted with 3-aminopropyltriethoxysilane using any conventionalmethod to perform aminopropylsilane treatment.

[0074] (2) Synthesis of Optically Active Polymer Compound

[0075] 15.0 g of lithium chloride in an absolute dry state was dissolvedin 150 ml of N,N-dimethylacetamide (DMAc) to prepare a DMAc/LiClsolution.

[0076] In a nitrogen atmosphere, 150ml of the above DMAc/LiCl solutionand 150 ml of pyridine were added to 10.0 g of cellulose, and theresulting mixture was immersed in an oil bath at 100° C. and stirred for24 hours. Thereafter, 50 g of 4-methylbenzoyl chloride was added to themixture to conduct reaction at 100° C. for 16 hours.

[0077] The reaction liquid was added dropwise to 2 L of methanol,followed by reprecipitation and centrifugal separation, therebyobtaining the objective cellulose tris(4-methylbenzoate) represented bythe following formula.

[0078] (3) Preparation of Separating Agent for Separating EnantiomericIsomers

[0079] 0.8 g of cellulose tris (4-methylbenzoate) obtained in (2) aboveand 506.0 mg of a compound (S-1) (2-fold molar equivalent to glucoseunit of cellulose tris(4-methylbenzoate)) were dissolved in methylenechloride to prepare a dope. This dope was applied to 3.2 g of silica gelobtained in (1) above. After the application, methylene chloride wasdistilled off to obtain the objective separating agent for separatingenantiomeric isomers. This separating agent was added to a mixed solventof n-hexane/2-propanol, and the resulting mixture was well stirred, andfiltered. The filtrate was condensed to recover 495.6 mg of (S-1).

[0080] (4) Preparation of Packed Column for HPLC

[0081] A stainless steel-made column having a length of 25 cm and aninner diameter of 0.46 cm was packed with the separating agent forseparating enantiomeric isomers obtained in (3) above by a slurrypacking method using a mixed solvent of n-hexane/2-propanol to obtain aseparation column for enantiomeric isomers.

[0082] S-1 residual amount in the separating agent for separatingenantiomeric isomers: 506.0-495.6=10.4 mg

[0083] Elution rate of S-1: 495.6/506.0×100=97.9%

[0084] S-1 residual amount in the separating agent of the separationcolumn for enantiomeric isomers:

[0085] (506.0-495.6)/4000×100=0.26%

Example 2

[0086] (1) Surface Treatment of Carrier (Silica Gel)

[0087] The silica gel treated with aminopropylsilane was obtained in thesame manner as in Example 1.

[0088] (2) Synthesis of Optically Active Polymer Compound

[0089] In a nitrogen atmosphere, 10.0 g of amylose was added to 300 mlof pyridine. The resulting mixture was immersed in an oil bath at 100°C., and 50 g of (S)-phenylethylisocyanate was added thereto to conductreaction at 100° C. for 48 hours. The reaction liquid was added dropwiseto 2 L of methanol, followed by reprecipitation and centrifugalseparation, thereby obtaining the objective amylosetris[(S)-phenylethylcarbamate] represented by the following equation.

[0090] (3) Preparation of Separating Agent for Separating EnantiomericIsomers

[0091] 0.8 g of amylose tris [(S)-phenylethylcarbamate] obtained in (2)above and 435.65mg of (S-1) (2-fold molar equivalent to a glucose unitof amylose tris [(S)-phenylethylcarbamate]) were dissolved in THF toprepare a dope. This dope was applied to 3.2 g of silica gel obtained in(1) above. After the application, THF was distilled off to obtain theobjective separating agent for separating enantiomeric isomers. Thisseparating agent was added to a mixed solvent of n-hexane/2-propanol,and the resulting mixture was well stirred, and filtered. The filtratewas condensed to recover 416.0 mg of (S-1).

[0092] (4) Preparation of Packed Column for HPLC

[0093] A separation column for enantiomeric isomers was obtained in thesame manner as in Example 1.

[0094] S-1 residual amount in separating agent for separatingenantiomeric isomers: 19.6 mg

[0095] Elution rate of S-1: 95.5%

[0096] S-1 residual amount in separating agent of separation column forenantiomeric isomers: 0.49%

Example 3

[0097] (1) Surface Treatment of Carrier (Silica Gel)

[0098] The silica gel treated with aminopropylsilane was obtained in thesame manner as in Example 1.

[0099] (2) Synthesis of Optically Active Polymer Compound

[0100] The objective cellulose tris(3,5-dimethylphenylcarbamate)represented by the following formula was obtained in the same manner asin Example 2.

[0101] (3) Preparation of Separating Agent for Separating EnantiomericIsomers

[0102] 0.8 g of cellulose tris(3,5-dimethylphenylcarbamate) obtained in(2) above and 435.9 mg of (S-1) (2-fold molar equivalent to a glucoseunit of cellulose tris(3,5-dimethylphenylcarbamate) were dissolved inacetone to prepare a dope. This dope was applied to 3.2 g of silica gelobtained in (1) above. After the application, acetone was distilled offto obtain the objective separating agent for separating enantiomericisomers. This separating agent was added to a mixed solvent ofn-hexane/2-propanol, and the resulting mixture was well stirred, andfiltered. The filtrate was condensed to recover 420.6 mg of (S-1).

[0103] (4) Preparation of Packed Column for HPLC

[0104] A separation column for enantiomeric isomers was obtained in thesame manner as in Example 1.

[0105] S-1 residual amount in separating agent for separatingenantiomeric isomers: 15.3 mg

[0106] Elution rate of S-1: 96.5%

[0107] S-1 residual amount in separating agent of separation column forenantiomeric isomers: 0.38%

Example 4

[0108] (1) Surface Treatment of Carrier (Silica Gel)

[0109] The silica gel treated with aminopropylsilane was obtained in thesame manner as in Example 1.

[0110] (2) Synthesis of Optically Active Polymer Compound

[0111] The objective amylose tris(3,5-dimethylphenylcarbamate)represented by the following formula was obtained in the same manner asin Example 2.

[0112] (3) Preparation of Separating Agent for Separating EnantiomericIsomers

[0113] 0.8 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in(2) above and 436.3 mg of (S-1) were dissolved in ethyl acetate toprepare a dope. This dope was applied to 3.2 g of silica gel obtained in(1) above. After the application, ethyl acetate was distilled off toobtain the objective separating agent for separating enantiomericisomers. This separating agent was added to a mixed solvent ofn-hexane/2-propanol, and the resulting mixture was well stirred, andfiltered. The filtrate was condensed to recover 427.6 mg of (S-1).

[0114] (4) Preparation of Packed Column for HPLC

[0115] A separation column for enantiomeric isomers was obtained in thesame manner as in Example 1.

[0116] S-1 residual amount in separating agent for separatingenantiomeric isomers: 8.7 mg

[0117] Elution rate of S-1: 98%

[0118] S-1 residual amount in separating agent of separation column forenantiomeric isomers: 0.22%

Examples 5 to 24

[0119] Using a compound having an asymmetric structure of a molecularweight of 1,000 or less shown in Table 1, the objective separating agentfor separating enantiomeric isomers was obtained by the same productionmethod of each of Examples 1 to 3, and thereafter a separation columnfor enantiomeric isomers was obtained. TABLE 1 Kind of compound havingProduction method asymmetric structure of (selected from molecularweight of 1,000 Example Examples 1 to 3) or less 5 2 S-3 6 2 D-6 7 2 L-68 2 S-7 9 2 R-8 10 2 S-8 11 2 S-9 12 3 L-6 13 2 S-11 14 2 R-9 15 1 R-316 1 S-3 17 1 D-6 18 1 R-8 19 1 Racemi form-13 20 1 Racemi form-5 21 1Racemi form-2 22 1 Racemi form-14 23 1 Racemi form-15 24 1 Racemiform-16

Comparative Example 1

[0120] The objective separating agent for separating enantiomericisomers was obtained in the same manner as in Example 1, and thereaftera separation column for enantiomeric isomers was obtained. However,(S-1) was not added.

Comparative Example 2

[0121] The objective separating agent for separating enantiomericisomers was obtained in the same manner as in Example 2, and thereaftera separation column for enantiomeric isomers was obtained. However,(S-1) was not added.

Comparative Example 3

[0122] The objective separating agent for separating enantiomericisomers was obtained in the same manner as in Example 3, and thereaftera separation column for enantiomeric isomers was obtained. However,(S-1) was not added.

Comparative Example 4

[0123] The objective separating agent for separating enantiomericisomers was obtained in the same manner as in Example 4, and thereaftera separation column for enantiomeric isomers was obtained. However,(S-1) was not added.

Application Examples 1 to 45

[0124] Using the separation columns for enantiomeric isomers obtained inExamples 1 to 24 and Comparative Examples 1 to 4, α values were measuredwith a liquid chromatography (liquid chromatograph, manufactured byJASCO Co.). The measurement conditions include moving phase:n-hexane/2-propanol=90/10, flow rate: 1.0 ml/min, temperature: 25° C.,and detection wavelength: 254 nm. The results are shown in Tables 2 to4.

[0125] The judgement in the tables is judgement of identity, similarityor non-similarity, and the details thereof are described after thetables. An increase rate (%) of α value in the tables was obtained bythe following equation: α₁-α₂×100. Here, expressed by α=1.00 is thestate where asymmetry identification was not conducted at all and onlyone peak was observed. TABLE 2 Kind of compound having asymmetricCompound Kind of separation Kind of separation Increase Applicationstructure of molecular to be separated column and α value column and αvalue rate of α example weight of 1,000 or less Kind Judgment Ex. α₁Com. Ex. α₂ value (%) 1 S-1 Racemi form-1 Identical 1 1.11 1 1.00 11 2S-1 Racemi form-1 Identical 2 4.24 2 3.73 14 3 S-1 Racemi form-1Identical 3 1.07 3 1.00  7 4 S-1 Racemi form-2 Similar 4 1.05 4 1.00  55 S-3 Racemi form-4 Similar 5 2.76 2 2.32 19 6 S-3 Racemi form-5 Similar5 3.51 2 2.45 43 7 D-6 Racemi form-5 Similar 6 3.13 2 2.45 28 8 L-6Racemi form-4 Similar 7 2.78 2 2.32 20 9 L-6 Racemi form-5 Similar 73.78 2 2.45 54 10 S-7 Racemi form-2 Similar 8 1.17 2 1.00 17 11 S-7Racemi form-5 Similar 8 3.06 2 2.45 25 12 R-8 Racemi form-2 Similar 91.29 2 1.00 29 13 R-8 Racemi form-4 Similar 9 2.68 2 2.32 16 14 S-8Racemi form-2 Similar 10 1.22 2 1.00 22 15 S-8 Racemi form-5 Similar 103.11 2 2.45 27 16 S-9 Racemi form-4 Similar 11 2.79 2 2.32 20 17 S-9Racemi form-5 Similar 11 2.73 2 2.45 11 18 S-1 Racemi form-2 Similar 21.12 2 1.00 12 19 S-1 Racemi form-5 Similar 2 2.90 2 2.45 18

[0126] Application Examples 4 and 18: The compound having the asymmetricstructure and the compound to be separated each have an asymmetriccarbon atom at the root of a phenyl group. Further, adjacent carbonatoms (β-position) of the asymmetric carbon atoms each have a carbonylgroup, and the environment around the asymmetric carbon atoms issimilar.

[0127] Application Examples 5, 8, 16 and 19: The compound having theasymmetric structure and the compound to be separated each have anasymmetric carbon atom at the root of a hydroxyl group. Further, theenvironment around the asymmetric carbon atom is similar.

[0128] Application Examples 6, 7 and 9: The compound having theasymmetric structure and the compound to be separated each have anasymmetric carbon atom at the root of a hydroxyl group. Further,adjacent carbon atoms (α-position) of the asymmetric carbon atoms areeach carbonyl groups, and thus, the environment around the asymmetriccarbon atoms is similar.

[0129] Application Examples 10, 12 and 14: The compound having theasymmetric structure and the compound to be separated each have anasymmetric carbon atom adjacent to an oxygen atom (α-position). Further,adjacent carbon atoms (β-position) of the asymmetric carbon atoms eachhave a carbonyl group, and the environment around the asymmetric carbonatoms is similar.

[0130] Application Example 11: The compound having the asymmetricstructure and the compound to be separated each have an asymmetriccarbon atom adjacent to a carbon atom and have a carbonyl group in amolecule. Thus, the environment around the asymmetric carbon atoms issimilar.

[0131] Application Example 13: The compound having the asymmetricstructure and the compound to be separated each have an asymmetriccarbon atom at the root of a trihalogenomethyl substituent. Further, theenvironment around the asymmetric carbon atom is similar.

[0132] Application Examples 15 and 17: The compound having he asymmetricstructure and the compound to be separated each have an asymmetriccarbon atom adjacent to an oxygen atom (α-position) and have a carbonylgroup in the vicinity of the asymmetric carbon atoms, and theenvironment around the asymmetric carbon atoms is similar. TABLE 2 Kindof compound having asymmetric Compound Kind of separation Kind ofseparation Increase Application structure of molecular to be separatedcolumn and α value column and α value rate of α example weight of 1,000or less Kind Judgment Ex. α₁ Com. Ex. α₂ value (%) 1 S-1 Racemi form-1Identical 1 1.11 1 1.00 11 2 S-1 Racemi form-1 Identical 2 4.24 2 3.7314 3 S-1 Racemi form-1 Identical 3 1.07 3 1.00  7 4 S-1 Racemi form-2Similar 4 1.05 4 1.00  5 5 S-3 Racemi form-4 Similar 5 2.76 2 2.32 19 6S-3 Racemi form-5 Similar 5 3.51 2 2.45 43 7 D-6 Racemi form-5 Similar 63.13. 2 2.45 28 8 L-6 Racemi form-4 Similar 7 2.78 2 2.32 20 9 L-6Racemi form-5 Similar 7 3.78 2 2.45 54 10 S-7 Racemi form-2 Similar 81.17 2 1.00 17 11 S-7 Racemi form-5 Similar 8 3.06 2 2.45 25 12 R-8Racemi form-2 Similar 9 1.29 2 1.00 29 13 R-8 Racemi form-4 Similar 92.68 2 2.32 16 14 S-8 Racemi form-2 Similar 10 1.22 2 1.00 22 15 S-8Racemi form-5 Similar 10 3.11 2 2.45 27 16 S-9 Racemi form-4 Similar 112.79 2 2.32 20 17 S-9 Racemi form-5 Similar 11 2.73 2 2.45 11 18 S-1Racemi form-2 Similar 2 1.12 2 1.00 12 19 S-1 Racemi form-5 Similar 22.90 2 2.45 18

[0133] TABLE 4 Kind of compound having asymmetric Compound Kind ofseparation Kind of separation Increase Application structure ofmolecular to be separated column and α value column and α value rate ofα example weight of 1,000 or less Kind Judgment Ex. α₁ Com. Ex. α₂ value(%) 39 Racemi form-13 Racemi form- Identical 19 1.82 1 1.67  9 13 40Racemi form-14 Racemi form- Similar 19 1.61 1 1.35 19 14 41 Racemiform-5  Racemi form- Non- 20 1.41 1 1.22 16 12 similar 42 Racemi form-2 Racemi form- Non- 21 1.52 1 1.22 25 12 similar 43 Racemi form-14 Racemiform- Non- 22 1.48 1 1.22 21 12 similar 44 Racemi form-15 Racemi form-Non- 23 1.46 1 1.22 20 12 similar 45 Racemi form-16 Racemi form- Non- 231.43 1 1.22 17 12 similar

[0134] Application Example 40: The compound having the asymmetricstructure and the compound to be separated each have an asymmetriccarbon atom at the root of a hydroxyl group, and the structure ofmolecule as a whole includes a condensed ring similar to a naphthylgroup and an anthranil group. Therefore, the environment around theasymmetric carbon atom is similar.

1. A method of producing a novel separating agent for separatingenantiomeric isomers, characterized by comprising adding a compoundhaving an asymmetric structure of a molecular weight of 1,000 or less insupporting an optically active polymer compound on a carrier.
 2. Amethod of producing a novel separating agent for separating enantiomericisomers, characterized by comprising: a step of supporting an opticallyactive polymer compound and a compound having an asymmetric structure ofa molecular weight of 1,000 or less on a carrier using a solvent; and astep of removing the solvent.
 3. A method of producing a novelseparating agent for separating enantiomeric isomers, characterized bycomprising: a step of supporting an optically active polymer compoundand a compound having an asymmetric structure of a molecular weight of1,000 or less on a carrier using a solvent; a step of removing thesolvent; and a step of removing the compound having the asymmetricstructure of the molecular weight of 1,000 or less by washing.
 4. Amethod of producing a novel separating agent for separating enantiomericisomers, characterized by comprising: a step of supporting an opticallyactive polymer compound on a carrier using a solvent; a step ofadditionally supporting a compound having an asymmetric structure of amolecular weight of 1,000 or less on the carrier; and a step of removingthe solvent.
 5. A method of producing a novel separating agent forseparating enantiomeric isomers, characterized by comprising: a step ofsupporting an optically active polymer compound on a carrier using asolvent; a step of additionally supporting a compound having anasymmetric structure of a molecular weight of 1,000 or less on thecarrier; a step of removing the solvent; and a step of removing thecompound having the asymmetric structure of the molecular weight of1,000 or less by washing.
 6. The method of producing a novel separatingagent for separating enantiomeric isomers as claimed in claim 1, whereinsupporting the optically active polymer compound on the carrier isconducted by physical adsorption.
 7. The method of producing a novelseparating agent for separating enantiomeric isomers as claimed in claim1, wherein supporting the optically active polymer compound on thecarrier is conducted by chemical bonding.
 8. The method of producing anovel separating agent for separating enantiomeric isomers as claimed inclaim 7, wherein the carrier and the optically active polymer compoundare chemically bonded before or after the removal of the compound havingthe asymmetric structure of the molecular weight of 1,000 or less. 9.The method of producing a novel separating agent for separatingenantiomeric isomers as claimed in claim 7, wherein the carrier and theoptically active polymer compound are chemically bonded by a reactionwith a crosslinking agent, a reaction with a radical generator orirradiation with light before or after the removal of the compoundhaving the asymmetric structure of the molecular weight of 1,000 orless.
 10. The method of producing a novel separating agent forseparating enantiomeric isomers as claimed in claim 1, wherein theoptically active polymer compound has an asymmetry identificationability to a compound to be separated when used as the separating agentfor separating the enantiomeric isomers.
 11. The method of producing anovel separating agent for separating enantiomeric isomers as claimed inclaim 1, wherein the optically active polymer compound is apolysaccharide derivative.
 12. The method of producing a novelseparating agent for separating enantiomeric isomers as claimed in claim1, wherein the optically active polymer compound is a polysaccharideester derivative or carbamate derivative.
 13. The method of producing anovel separating agent for separating enantiomeric isomers as claimed inclaim 1, wherein the optically active polymer compound is a cellulosederivative or an amylose derivative.
 14. The method of producing a novelseparating agent for separating enantiomeric isomers as claimed in claim1, wherein the optically active polymer compound is a polymer or acopolymer of acrylamides, methacrylamides, acrylates or methacrylateshaving an optically active substituents on a side chain.
 15. The methodof producing a novel separating agent for separating enantiomericisomers as claimed in claim 1, wherein an amount of the optically activepolymer compound supported on the carrier is 1 to 100 mass % to a massof the carrier.
 16. The method of producing a novel separating agent forseparating enantiomeric isomers as claimed in claim 1, wherein thecompound having the asymmetric structure of the molecular weight of1,000 or less is a compound to be separated or a similarly structuredcompound thereof when used as the separating agent for separating theenantiomeric isomers.
 17. The method of producing a novel separatingagent for separating enantiomeric isomers as claimed in claim 1, whereinthe compound having the asymmetric structure of the molecular weight of1,000 or less is not a compound to be separated or a similarlystructured compound thereof when used as the separating agent forseparating the enantiomeric isomers.
 18. The method of producing a novelseparating agent for separating enantiomeric isomers as claimed in claim17, wherein the compound having the asymmetric structure of themolecular weight of 1,000 or less is not the compound to be separated orthe similarly structured compound thereof when used as the separatingagent for separating the enantiomeric isomers, and is a compound havinga cyclic structure of a molecular weight of 40 to
 1000. 19. The methodof producing a novel separating agent for separating enantiomericisomers as claimed in claim 1, wherein the compound having theasymmetric structure of the molecular weight of 1,000 or less is aracemi form and/or an optically active substance.
 20. The method ofproducing a novel separating agent for separating enantiomeric isomersas claimed in claim 1, wherein the amount of the compound having theasymmetric structure of the molecular weight of 1,000 or less supportedon the carrier is 0.01 to 1,000 mass % to a mass of the optically activepolymer compound.
 21. The method of producing a novel separating agentfor separating enantiomeric isomers as claimed in claim 1, wherein aresidual amount of the compound having the asymmetric structure of themolecular weight of 1,000 or less is 10 mass % or less in the separatingagent for separating the enantiomeric isomers.
 22. The method ofproducing a novel separating agent for separating enantiomeric isomersas claimed claim 1, wherein the compound having the asymmetric structureof the molecular weight of 1,000 or less is substantially removed. 23.The method of producing a novel separating agent for separatingenantiomeric isomers as claimed in claim 1, wherein the compound havingthe asymmetric structure of the molecular weight of 1,000 or less is thecompound to be separated or the similarly structured compound thereofwhen used as the separating agent for separating the enantiomericisomers, and when the enantiomeric isomers are separated using theobtained separating agent for separating the enantiomeric isomers, aseparation performance based on a separation coefficient (α) obtained bythe following equation: separation coefficient (α)=(holding coefficientof enantiomer held relatively strongly)/(holding coefficient of theenantiomer held relatively weakly) holding coefficient (k′)=[(holdingtime of the enantiomer)−(dead time)]/(dead time) is represented by thefollowing equation (A) or equation (B): (A)α₁/α₂≧1.05(providedα₂=1.00)(B) α₁/α₂≧1.05(provided α₂>1.00) where α₁: a separationcoefficient of the separating agent for separating the enantiomericisomers obtained by adding the compound having the asymmetric structureof the molecular weight of 1,000 or less in a production step, and α₂: aseparation coefficient of the separating agent for separating theenantiomeric isomers obtained without adding the compound having theasymmetric structure of the molecular weight of 1,000 or less in theproduction step, in which α₂=1.00 means that the enantiomeric isomersare not separated al all, and α₂>1.00 means that the enantiomericisomers are separated.
 24. The method of producing a novel separatingagent for separating enantiomeric isomers as claimed in claim 1, whereinthe compound having the asymmetric structure of the molecular weight of1,000 or less is not the compound to be separated or the similarlystructured compound thereof when used as the separating agent forseparating the enantiomeric isomers, and when the enantiomeric isomersare separated using the obtained separating agent for separating theenantiomeric isomers, a separation performance based on a separationcoefficient (α) obtained by the following equation: separationcoefficient (α)=(holding coefficient of enantiomer held relativelystrongly)/(holding coefficient of the enantiomer held relativelyweakly)holding coefficient (k′)=[(holding time of the enantiomer)−(deadtime)]/(dead time) is represented by the following equation (A) orequation (B): (A)α₁/α₂≧1.05(provided α₂=1.00)(B)α₁/α₂≧1.05(providedα₂>1.00) where α₁: a separation coefficient of the separating agent forseparating the enantiomeric isomers obtained by adding the compoundhaving the asymmetric structure of the molecular weight of 1,000 or lessin a production step, and α₂: a separation coefficient of the separatingagent for separating the enantiomeric isomers obtained without addingthe compound having the asymmetric structure of the molecular weight of1,000 or less in the production step, in which α₂=1.00 means that theenantiomeric isomers are not separated al all, and α₂>1.00 means thatthe enantiomeric isomers are separated.
 25. The method of producing anovel separating agent for separating enantiomeric isomers as claimed inclaim 24, wherein the compound having the asymmetric structure of themolecular weight of 1,000 or less is not the compound to be separated orthe similarly structured compound thereof when used as the separatingagent for separating the enantiomeric isomers, and is a compound havinga cyclic structure of a molecular weight of 40 to
 1000. 26. A separatingagent for separating enantiomeric isomers, comprising an opticallyactive polymer compound supported on a carrier, from which a compoundhaving an asymmetric structure of a molecular weight of 1,000 or lessadded as a production raw material and supported is removed.
 27. Theseparating agent for separating enantiomeric isomers as claimed in claim26, wherein a residual amount of the compound having the asymmetricstructure of the molecular weight of 1,000 or less is 10 mass % or lessin the separating agent for separating the enantiomeric isomers.
 28. Thenovel separating agent for separating enantiomeric isomers as claimed inclaim 26 or 27, wherein the compound having the asymmetric structure ofthe molecular weight of 1,000 or less is substantially removed.
 29. Thenovel separating agent for separating enantiomeric isomers as claimed inany one of claims 26 to 28 claim 26, wherein supporting the opticallyactive polymer compound on the carrier is conducted by physicaladsorption.
 30. The novel separating agent for separating enantiomericisomers as claimed in any one of claims 26 to 28 claim 26, whereinsupporting the optically active polymer compound on the carrier isconducted by chemical bonding.
 31. The novel separating agent forseparating enantiomeric isomers as claimed in claim 30, wherein thecarrier and the optically active polymer compound are chemically bondedbefore or after the removal of the compound having the asymmetricstructure of the molecular weight of 1,000 or less.
 32. The novelseparating agent for separating enantiomeric isomers as claimed in claim30, wherein the carrier and the optically active polymer compound arechemically bonded by a reaction with a crosslinking agent, a reactionwith a radical generator or irradiation with light before or after theremoval of the compound having the asymmetric structure of the molecularweight of 1,000 or less.
 33. The separating agent for separatingenantiomeric isomers as claimed in any one of claims 26 to 32 claim 26,wherein the optically active polymer compound has an asymmetryidentification ability to a compound to be separated when used as theseparating agent for separating the enantiomeric isomers.
 34. Theseparating agent for separating enantiomeric isomers as claimed in anyone of claims 26 to 33 claim 26, wherein the optically active polymercompound is a polysaccharide derivative.
 35. The separating agent forseparating enantiomeric isomers as claimed in any one of claims 26 to 34claim 26, wherein the optically active polymer compound is apolysaccharide ester derivative or carbamate derivative.
 36. Theseparating agent for separating enantiomeric isomers as claimed in anyone of claims 26 to 35 claim 26, wherein the optically active polymercompound is a cellulose derivative or an amylose derivative.
 37. Theseparating agent for separating enantiomeric isomers as claimed in anyone of claims 26 to 33 claim 26, wherein the optically active polymercompound is a polymer or a copolymer of acrylamides, methacrylamides,acrylates or methacrylates having an optically active substituent on aside chain.
 38. The separating agent for separating enantiomeric isomersas claimed in any one of claims 26 to 37 claim 26, wherein an amount ofthe optically active polymer compound supported on the carrier is 1 to100 mass % to a mass of the carrier.
 39. The separating agent forseparating enantiomeric isomers as claimed in any one of claims 26 to 38claim 26, wherein the compound having the asymmetric structure of themolecular weight of 1,000 or less is a compound to be separated or asimilarly structured compound thereof when used as the separating agentfor separating the enantiomeric isomers.
 40. The separating agent forseparating enantiomeric isomers as claimed in any one of claims 26 to 38claim 26, wherein the compound having the asymmetric structure of themolecular weight of 1,000 or less is not the compound to be separated ora similarly structured compound thereof when used as the separatingagent for separating the enantiomeric isomers.
 41. The novel separatingagent for separating enantiomeric isomers as claimed in claim 40,wherein the compound having the asymmetric structure of the molecularweight of 1,000 or less is not the compound to be separated or asimilarly structured compound thereof when used as the separating agentfor separating the enantiomeric isomers, and is a compound having acyclic structure of a molecular weight of 40 to
 1000. 42. The novelseparating agent for separating enantiomeric isomers as claimed in anyone of claims 26 to 41 claim 26, wherein the compound having theasymmetric structure of the molecular weight of 1,000 or less is aracemi form and/or an optically active substance.
 43. The separatingagent for separating enantiomeric isomers as claimed in any one ofclaims 26 to 42 claim 26, wherein the amount of the compound having theasymmetric structure of the molecular weight of 1,000 or less supportedon the carrier is 0.01 to 1,000 mass % to a mass of the optically activepolymer compound.
 44. The novel separating agent for separatingenantiomeric isomers as claimed in any one of claims 26 to 43 claim 26,wherein the compound having the asymmetric structure of the molecularweight of 1,000 or less is a compound to be separated or a similarlystructured compound thereof when used as a separating agent forseparating enantiomeric isomers, and when the enantiomeric isomers areseparated using the separating agent for separating the enantiomericisomers, a separation performance based on a separation coefficient (α)obtained by the following equation: separation coefficient (α)=(holdingcoefficient of enantiomer held relatively strongly)/(holding coefficientof the enantiomer held relatively weakly)holding coefficient(k′)=[(holding time of the enantiomer)−(dead time)]/(dead time) isrepresented by the following equation (A) or equation (B):(A)α₁/α₂≧1.05(provided α₂=1.00)(B)α₁/α₂≧1.05(provided α₂>1.00) where α₁:a separation coefficient of the separating agent for separating theenantiomeric isomers obtained by adding the compound having theasymmetric structure of the molecular weight of 1,000 or less in aproduction step, and α₂: a separation coefficient of the separatingagent for separating the enantiomeric isomers obtained without addingthe compound having the asymmetric structure of the molecular weight of1,000 or less in the production step, in which α₂=1.00 means that theenantiomeric isomers are not separated al all, and α₂>1.00 means thatthe enantiomeric isomers are separated.
 45. The novel separating agentfor separating enantiomeric isomers as claimed in any one of claims 26to 43 claim 26, wherein the compound having the asymmetric structure ofthe molecular weight of 1,000 or less is not the compound to beseparated or the similarly structured compound thereof when used as theseparating agent for separating the enantiomeric isomers, and when theenantiomeric isomers are separated using the separating agent forseparating the enantiomeric isomers, a separation performance based on aseparation coefficient (α) obtained by the following equation:separation coefficient (α)=(holding coefficient of enantiomer heldrelatively strongly)/(holding coefficient of the enantiomer heldrelatively weakly)holding coefficient (k′)=[(holding time of theenantiomer)−(dead time)]/(dead time) is represented by the followingequation (A) or equation (B): (A)α₁/α₂≧1.05(providedα₂=1.00)(B)α₁/α₂≧1.05(provided α₂>1.00) where α₁: a separationcoefficient of the separating agent for separating the enantiomericisomers obtained by adding the compound having the asymmetric structureof the molecular weight of 1,000 or less in a production step, and α₂: aseparation coefficient of the separating agent for separating theenantiomeric isomers obtained without adding the compound having theasymmetric structure of the molecular weight of 1,000 or less in theproduction step, in which α₂=1.00 means that the enantiomeric isomersare not separated al all, and α₂>1.00 means that the enantiomericisomers are separated.
 46. The separating agent for separatingenantiomeric isomers as claimed in claim 45, wherein the compound havingthe asymmetric structure of the molecular weight of 1,000 or less is nota compound to be separated or a similarly structured compound thereofwhen used as the separating agent for separating the enantiomericisomers, and is a compound having a cyclic structure of a molecularweight of 40 to
 1000. 47. An immobilizing phase for a chromatographyusing the separating agent for separating enantiomeric isomers asclaimed in claim
 46. 48. An immobilizing phase for a continuous liquidpreparative chromatography using the separating agent for separatingenantiomeric isomers as claimed in claim
 26. 49. A separation method forenantiomeric isomers using the separating agent for separating theenantiomeric isomers as claimed in claim 26.